EP0177356A2 - Methode zur Behandlung der Antidiurese - Google Patents

Methode zur Behandlung der Antidiurese Download PDF

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Publication number
EP0177356A2
EP0177356A2 EP85307088A EP85307088A EP0177356A2 EP 0177356 A2 EP0177356 A2 EP 0177356A2 EP 85307088 A EP85307088 A EP 85307088A EP 85307088 A EP85307088 A EP 85307088A EP 0177356 A2 EP0177356 A2 EP 0177356A2
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EP
European Patent Office
Prior art keywords
threo
dops
serine
dihydroxyphenyl
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP85307088A
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English (en)
French (fr)
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EP0177356A3 (en
EP0177356B1 (de
Inventor
Junki Katsube
Mitsutaka Nakamura
Yukio Maeda
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Sumitomo Pharmaceuticals Co Ltd
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Sumitomo Pharmaceuticals Co Ltd
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Priority to AT85307088T priority Critical patent/ATE67410T1/de
Publication of EP0177356A2 publication Critical patent/EP0177356A2/de
Publication of EP0177356A3 publication Critical patent/EP0177356A3/en
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Publication of EP0177356B1 publication Critical patent/EP0177356B1/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the present invention relates to a method for the treatment of antidiuresis and a therapeutic composition containing an effective amount of threo-3-(3,4-dihydroxyphenyl)-serine (hereinafter referred to as threo-DOPS).
  • threo-DOPS threo-3-(3,4-dihydroxyphenyl)-serine
  • Diuretics directly act on the kidney and promote the excretion of sodium chloride and water from the kidney.
  • drugs having diuretic action and some of them have been clinically used. They are thiazide diuretics represented by chlorothiazide, loop diuretics represented by furosemide, and potassium-preserving diuretics represented by spironolactone and triamteren and so on.
  • the present invention provides a new type of treatment of antidiuresis different from those already known.
  • the 3-(3,4-dihydroxyphenyl)-serine related to the present invention is an aromatic amino acid abbreviated to DOPS.
  • DOPS aromatic amino acid
  • threo-DOPS threo isomer
  • erythro-DOPS erythro isomer
  • DOPS includes from stereoisomerism, L-threo-DOPS, D-threo-DOPS, L-erythro-DOPS and D-erythro-DOPS.
  • DL-isomer racemic form which is an equivalent mixture of the D-isomer and the L-isomer.
  • L-DOPS undergoes decarboxylation by aromatic L-amino acid decarboxylase and is converted to noradrenaline (hereinafter referred to as NA) in vivo.
  • NA noradrenaline
  • a natural type l-NA originally present in a living body is formed from L-threo-DOPS and an unnatural type d-NA, from L-erythro-DOPS.
  • L- or DL-threo-DOPS has a significant diuretic action. There is not a report up to the present on such an action, and it is a finding first found out by the present inventors.
  • DCI peripheral decarboxylase inhibitor
  • the diuretic action of L-threo-DOPS of the present invention has a wide clinical applicability as well as the existing diuretics. That is, it can be similarly applied to oedema which is the most general objective symptom of diuretics.
  • Anasarca occurs in various forms, namely cardiac, hepatic, and renal anasarca.
  • the present drug is most preferably applicable to cardiac anasarca, namely congestive heart failure, since the present drug appears to be converted to i-NA which represents a cardiotonic action.
  • AVP arginine vasopressin
  • ADH antidiuretic hormone
  • the acceleration of AVP action relates to one of the causes of cardiac or hepatic anasarca mentioned above.
  • the present drugs are also thought likely to be effective against such antidiuretic conditions as myxedema, Addison's disease and other syndromes of inappropriate ADH secretion.
  • L- or DL-threo-DOPS of the present invention has very low toxicity supports the usefulness of the present drugs as practical medicines.
  • the acute toxicity by oral dosage to mouse, rat and dog is 10 g/kg or more.
  • L- or DL-threo-DOPS used in the present invention can be prepared by any of already known methods.
  • the threo-DOPS can be used in a form of a pharmaceutically acceptable acid addition salt.
  • acids useful to form such acid addition salts there can be illustrated inorganic acids such as hydrochloric acid, hydrobromic acid and sulphuric acid, and organic acids such as fumaric acid, citric acid, tartaric acid and succinic acid.
  • the threo-DOPS which is an active compound in the present invention, can be applied orally or parenterally in a dosage amount suitable to the individual need. That is, the amount of dosage for remedy can be orally applied in ordinary dosing forms such as tablets, capsules, syrups, and suspensions; or also materials in liquid forms such as solutions, emulsions, and suspensions thereof can be parenterally applied in a form of injections.
  • the drugs of suitable dosage types mentioned above can be prepared by combining an active compound with ordinary allowable pharmaceutically acceptable carriers, vehicles, binders, stabilizers and the like. When used in the form of injections, allowable buffers, dissolution aids, isotonic agents, etc. may be added.
  • the amount of dosage and the frequency of dosage of threo-DOPS used in the present application are different depending upon the form of dosage and the extent of the symptoms requiring remedy; however, for instance, in the case of oral administration, it can be applied in an amount of 0.1-4 g per adult per day at once or several times dividedly.
  • intravenous injection it can be applied in an amount of 0.1-22 g per adult per day at once or several times dividedly.
  • Figure 1 is a diagram which shows the effect of L-threo-DOPS on urinary volume of rats.
  • the ordinate represents the urinary volume (ml/kg/3 hr) and the abscissa, the amount of dosage of L-threo-DOPS (mg/kg);
  • Figure 2 is a diagram which shows the effect of L-threo-DOPS on urinary volume of mice.
  • the ordinate represents the urinary volume (ml/kg/3 hr) and the abscissa, the amount of dosage of L-threo-DOPS (mg/kg).
  • Three rats starved for 17 hours were arranged to form a group.
  • Ten mg/kg, 30 mg/kg, and 100 mg/kg of L-threo-DOPS were suspended in 0.5% aqueous solution of methyl cellulose, respectively, and orally administered together with 25 ml/kg of isotonic sodium chloride solution.
  • a control group was dosed with only a 0.5% aqueous solution of methyl cellulose and isotonic sodium chloride solution. The urinary volume was measured for 3 hours after the administration of the dose.
  • Table 1 The effect of the dose on electrolytes in the urine is as shown in Table 1.
  • values are represented in units of mEq/kg/3 hr and as the average of 5 groups + S.E.
  • Table 1 shows that the amount of Na + in urine significantly increases in the groups wherein the dose is 10 mg/kg or more of L-threo-DOPS; the amount of K + is not so much influenced by L-threo-DOPS but a significant increase is recognized only in the group wherein the dose was 100 mg/kg.
  • the amount of Cl- in the urine is significantly increased only in the groups wherein the dose is 30 mg/kg or more of L-threo-DOPS.
  • mice starved for 17 hours were arranged to form a group.
  • Ten mg/kg, 30 mg/kg, and 100 mg/kg of L-threo-DOPS were suspended in a 0.5% aqueous solution of methyl cellulose, respectively, and orally administered together with 25 mg/kg of isotonic sodium chloride solution.
  • a control group was dosed with only a 0.5% aqueous solution of methyl cellulose and isotonic sodium chloride solution.
  • L-threo-DOPS increases the urinary volume in accordance with the amount of the dose, and the increase in urinary volume is significant in the group wherein the dose is 100 mg/kg.
  • Rats were dosed with 30 mg/kg of L-threo-DOPS by oral administration, and the amount of NA in the kidney and heart after 1 hour was measured.
  • the method for the measurement was generally in accordance with the method of Suzuki, et al. (Europ. J. Clin. Pharmacol., 23, 463, 1982).
  • DOPS may be prepared by condensing 3,4-dibenzyloxybenzaldehyde and glycine and then subjecting the resulting 3-(3,4-dibenzyloxy- phenyl)serine to debenzylation.
  • the DOPS is obtained as a mixture of diastereoisomers (i.e. the threo isomer and the erythro isomer).
  • a single isomer can be isolated from a mixture of the threo and erythro isomers of 3-(3,4 dibenzyl- oxyphenyl)-serine, by treating the mixture with a mineral acid, and separating the mineral salt of a single isomer using a technique which depends on the difference in solubility of the mineral acid salts of the two isomers.
  • the threo-3-(3,4-dibenzyloxy- phenyl)serine or a mineral acid salt thereof obtained by the above method is subjected to debenzylation to give threo-DOPS.
  • threo- and erythro-3-(3,4-dibenzyloxyphenyl)serine is reacted with one mole or more, preferably one to two moles, of a mineral acid per mole of the threo and erythro isomers, in an appropriate solvent, such as water, methanol, ethanol, acetone, N,N-dimethylformamide, or a mixture thereof.
  • This reaction is generally carried out at room temperature or an elevated temperature, preferably from 20 to 60°C.
  • the mixture of the resulting mineral acid salts of the threo and erythro isomers can be isolated from the reaction mixture by evaporating the solvent under reduced pressure or by adding a solvent, in which the mineral acid salts are sparingly soluble, such as diethyl ether, toluene or n-hexane.
  • the starting threo- and erythro-3-(3,4-di- benzyloxyphenyl)serine may have any molar ratio of the threo isomer and erythro isomer.
  • Suitable mineral acids include hydrochloric acid, hydrobromic acid, hydroiodic acid and nitric acid. The hydrochloric acid is preferred because of its price and ease of handling.
  • the mixture of the mineral acid salts thus isolated is then subjected to fractional crystallization by a conventional method to give the relatively insoluble mineral acid salt of threo-3-(3,4-dibenzyloxyphenyl)-serine.
  • the fractional crystallization can generally be carried out by dissolving the mixture in a solvent which is heated to a temperature a little higher than that sufficient to dissolve it, and subsequently gradually cooling the solution to room temperature or lower, preferably 30° to +20°C, to crystallize out the mineral acid salt of the threo isomer, while the mineral acid salt of the erythro isomer remains in solution.
  • the particular solvent to be used for the fractional crystallization is not important, unless the particular mineral acid salt is decomposed or hydrolyzed. However, it is preferable not to use a solvent which cannot or can only slightly dissolve the mineral acid salts, such as diethyl ether or toluene, or a solvent containing a large amount of diethyl ether or toluene.
  • suitable solvents for the fractional crystallization are water, ethanol, isopropanol, acetone, ethyl acetate, and mixtures thereof.
  • the thus separated mineral acid salt of threo-3-(3,4-dibenzyloxyphenyl)serine may be converted into free threo-3-(3,4-dibenzyloxyphenyl)-serine by a conventional process, for instance, by treating the mineral acid salt with a base, such as sodium hydroxide, sodium acetate or diethylamine.
  • a base such as sodium hydroxide, sodium acetate or diethylamine.
  • optically active L-threo-DOPS is made by firstly subjecting a racemic protected DOPS to optical resolution with a specific resolving reagent and then subjecting the resulting optically active protected DOPS to hydrogenolysis.
  • the process comprises subjecting racemic threo- . 3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine of the formula: to optical resolution with an optically active amino alcohol derivative of the formula: wherein R is methyl, isopropyl or isobutyl, and then subjecting the resulting optically active L-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine to hydrogenolysis to give the desired optically active L-threo-DOPS.
  • the starting racemic threo-3-(3,4-dibenzyloxy- phenyl)-N-carbobenzyloxyserine [I] is a known compound and can easily be obtained by introducing a carbobenzyloxy group onto the amino group of racemic threo-3-(3,4-dibenzyloxyphenyl)serine.
  • the optically active amino alcohol derivatives [II] used as the resolving reagent are also known [cf. J. Chem. Soc., 287 (1925), 785 (1926); J. Pharm.
  • Racemic threo-3-(3,4-dibenzyloxyphenyl)-N-carbo- benzyloxyserine (65 g) is dissolved in methanol (650 g) at 50°C, and therein is dissolved S-2-amino-1,1-diphenylpropanol (28.0 g). The mixture is cooled to 30°C over a period of one hour. The mixture is again heated to 50°C and is then cooled to 25°C over a period of 2 hours and is agitated under ice-cooling for 3 hours.

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EP85307088A 1984-10-04 1985-10-03 Methode zur Behandlung der Antidiurese Expired - Lifetime EP0177356B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85307088T ATE67410T1 (de) 1984-10-04 1985-10-03 Methode zur behandlung der antidiurese.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP59208586A JPS6185318A (ja) 1984-10-04 1984-10-04 利尿薬
JP208586/84 1984-10-04

Publications (3)

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EP0177356A2 true EP0177356A2 (de) 1986-04-09
EP0177356A3 EP0177356A3 (en) 1987-11-25
EP0177356B1 EP0177356B1 (de) 1991-09-18

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EP85307088A Expired - Lifetime EP0177356B1 (de) 1984-10-04 1985-10-03 Methode zur Behandlung der Antidiurese

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US (1) US4647587A (de)
EP (1) EP0177356B1 (de)
JP (1) JPS6185318A (de)
AT (1) ATE67410T1 (de)
AU (1) AU574978B2 (de)
CA (1) CA1267607A (de)
DE (1) DE3584131D1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0506384A1 (de) * 1991-03-27 1992-09-30 Sumitomo Pharmaceuticals Company, Limited Pharmazeutische Zusammensetzung zur Behandlung der Harninkontinenz enthaltend DL- oder L-threo-3-(3,4-Dihydroxyphenyl)Serin

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3559572B2 (ja) * 1993-01-29 2004-09-02 住友製薬株式会社 急性痛および慢性痛用鎮痛剤
US20060105036A1 (en) 2003-05-12 2006-05-18 Stephen Peroutka Threo-dops controlled release formulation
US8158149B2 (en) * 2004-05-12 2012-04-17 Chelsea Therapeutics, Inc. Threo-DOPS controlled release formulation
WO2005025561A1 (en) * 2003-09-04 2005-03-24 Synergia Pharma, Inc. Compositions and methods for orthostatic intolerance
EP1948155B1 (de) * 2006-06-28 2012-03-07 Chelsea Therapeutics Inc. Pharmazeutische zusammensetzungen mit droxidopa
AU2008226541B2 (en) * 2007-03-09 2013-05-09 Chelsea Therapeutics, Inc. Droxidopa and pharmaceutical composition thereof for the treatment of fibromyalgia
NZ581707A (en) * 2007-05-07 2011-05-27 Chelsea Therapeutics Inc Droxidopa and pharmaceutical composition thereof for the treatment of mood disorders, sleep disorders, or attention deficit disorders
JP5880913B2 (ja) 2011-05-17 2016-03-09 三郎 佐古田 パーキンソン病の体幹症状（姿勢反射異常）の治療剤

Family Cites Families (6)

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Publication number Priority date Publication date Assignee Title
US3920728A (en) * 1973-08-22 1975-11-18 Hoffmann La Roche Separation and resolution of isomeric forms of 3-(3,4-dihydroxy-phenyl)-serine
JPS52125630A (en) * 1976-04-14 1977-10-21 Kyowa Hakko Kogyo Co Ltd Antiperkinson drugs containing l-threo-3,4-dihydroxyphenylserine
JPS56104815A (en) * 1980-01-23 1981-08-20 Sumitomo Chem Co Ltd Remedy for peripheral orthostatic hypotension
JPS5852219A (ja) * 1981-09-22 1983-03-28 Sumitomo Chem Co Ltd パ−キンソン病治療剤
JPS6067420A (ja) * 1983-09-22 1985-04-17 Sumitomo Chem Co Ltd 精神運動興奮抑制剤
AU575849B2 (en) * 1983-09-22 1988-08-11 Sumitomo Chemical Company, Limited Pharmaceutical composition and method for treatment of psychomotor excitement

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ARCH. INT. PHARMACODYN., vol. 222, no. 1, 1976 pages 94-102. R.G. PENDLETON et al: "Studies concerning dopamine diuresis in the rats." *
EUR. J. CLIN. PHARMACOL., vol. 23, no. 5, 1982, pages 463-468, Springer Verlag. T. SUZUKI et al: "Pharmacokinetic studies of oral-L-threo-3,4-dihydroxyphenylserine in normal subjects and patients with familial amyloid plyneuropathy." *
J. PHARM. PHARMACOL., vol. 30, 1978, pages 456-458. H. ARAKI et al: "Positive chronotropic effect of threo-3,4-dihydroxyphenylserine as a precursor of noradrenaline in rat isolated atria." *
J. PHARM. PHARMACOL., vol. 33, no. 12, December 1981, pages 772-777. H. ARAKI et al: "Pressor effect of L-threo-3,4-dihydroxyphenylserine in rats." *
J. PHARM. PHARMACOL., vol. 33, no. 12, December 1981, pages 778-782. H. ARAKI et al: "Age-related changes in the chronotropic effect and the enzymic decarboxylation of L-threo-3,4-dihydroxyphenylserine in the rat heart." *
J. PHARM. PHARMACOL., vol. 38, 1986, pages 533-534. J. KATSUBE et al: "Diuretic effect of L-threo-3,4-dihydroxyphenylserin, a noradrenaline precursor, in rats and mice." *
JAPAN. J. PHARMACOL., vol. 28, October 1978, pages 747-753. I. OHMURA et al: "Enzymatic decarboxylation of L-threo-3,4-dihydroxyphenylserine in rat heart." *
JAPAN. J. PHARMACOL., vol. 39, Suppl. 1985, page 222, ref.no. 04G1348. M. NAKAMURA et al: "A diuretic effect of L-threo-3,4-dihydroxyphenyxlserine (L-threo-DOPS), a norepinephrine precursor in rats or mice." *
JOURNAL OF CLINICAL INVESTIGATION, vol. 52, February 1973, pages 502-511. R.W. SCHRIER et al: "Mechanism of effect of alpha adrenergic stimulation with norepinephrine on renal water excretion." *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0506384A1 (de) * 1991-03-27 1992-09-30 Sumitomo Pharmaceuticals Company, Limited Pharmazeutische Zusammensetzung zur Behandlung der Harninkontinenz enthaltend DL- oder L-threo-3-(3,4-Dihydroxyphenyl)Serin
US5266596A (en) * 1991-03-27 1993-11-30 Sumitomo Pharmaceuticals Co., Ltd. L- or DL-threo-3-(3,4-dihydroxyphenyl)serine for the treatment of urinary incontinence

Also Published As

Publication number Publication date
AU574978B2 (en) 1988-07-14
US4647587A (en) 1987-03-03
ATE67410T1 (de) 1991-10-15
EP0177356A3 (en) 1987-11-25
DE3584131D1 (de) 1991-10-24
AU4827085A (en) 1986-04-24
CA1267607A (en) 1990-04-10
JPS6185318A (ja) 1986-04-30
JPH0477728B2 (de) 1992-12-09
EP0177356B1 (de) 1991-09-18

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